The broad species tropisms and the ability to cause fatal disease in both animals and humans have distinguished the Henipaviruses; Nipah virus (NiV) and Hendra virus (HeV) from all other known paramyxoviruses. These viruses can be amplified and cause disease in animals and be transmitted to humans where infection is manifested as a severe respiratory illness and/or febrile encephalitis. They are classified as BSL-4 select agents and possess several characteristics which make them highly adaptable for their use as bioterror agents. HeV appeared first in Australia in 1994 and was transmitted to humans from infected horses; NiV appeared in 1998-99 in Malaysia and was predominantly passed from infected pigs to humans, but several animal species were also infected. Both viruses continue to re-emerge; in 2004 two NiV outbreaks in Bangladesh caused some 65 human cases. Another outbreak in 2005 in the same area claimed 12 lives, and a recent emergence in India in 2007 has taken 5 lives. HeV has reappeared in Australia in 1999, 2004 and 2006, with cases of fatal infection in horses and one non-fatal, sero-converting, human case. Public health relevance: Significant observations in the most recent NiV outbreaks have been a higher incidence of acute respiratory distress syndrome, person-to-person transmission, higher case fatality rates (~75%), and no link to infected livestock or domestic animals. The development of therapeutics and vaccine strategies is now important. Over the past several years we have performed an extensive characterization of the viral envelope glycoproteins (F and G), virus assembly mechanisms, developed viral fusion inhibitors and identified the cellular receptor for both HeV and NiV (ephrinB2). Recently, we have characterized a soluble G glycoprotein (sG) as a subunit vaccine, a cat model for NiV infection and have demonstrated that sG can protect against NiV challenge. We have also isolated and characterized potent neutralizing fully-human anti- G monoclonal antibodies and have mapped the receptor binding site on G. The objectives of this proposal are to: fully characterize a ferret model of Nipah virus infection, and evaluate existing and discover new therapeutic modalities for treating Nipah and Hendra virus infection. The Specific Aims are: 1) Establish virus infection, lethal dose, and detection parameters of NiV in a ferret model. 2) Evaluate the protective efficacy of sG as a subunit vaccine for NiV in the ferret. 3) Determine the passive protective efficacy of neutralizing, anti-G, fully-human monoclonal antibody therapy for NiV infection in the cat and ferret. 4) Determine the solution structure of NiV sG in complex with its receptor ephrinB2, and perform both structure-dependent design and structure-independent High-Throughput-Screening discovery of small- molecule inhibitors of the G-receptor interaction.